The present invention relates to novel heterocyclic compounds or salts thereof, which are useful as a medicine.
Heterocyclic compounds of the formula below have been known to be useful as anticancer agent (WO95/027699). 
wherein A is optionally substituted heteroaryl or its oxide, B is optionally substituted ethenylene, D is optionally substituted phenylene, G is optionally substituted phenyl and R0 is hydrogen, acetyl, optionally substituted alkyl or optionally substituted alkenyl.
It has also been known that (E)-4-(2-(2-(N-(4-methoxy-benzenesulfonyl) amino)phenyl)ethenyl)pyridine 1-oxide (hereinafter, referred to as xe2x80x9cCompound Axe2x80x9d) has a potent growth inhibition activity on cancer cells, and that (E)-4-(2-(2-(N-(4-acetyl-N-(4-methoxy-benzenesulfonyl)amino)phenyl)ethenyl)pyridine 1-oxide (hereinafter, referred to as xe2x80x9cCompound Bxe2x80x9d) has an anticancer activity with low toxicity. Accordingly, the Compounds A and B have been expected to be promising drugs for oral administration in the treatment of various malignant tumors such as lung cancer, breast cancer, gastrointestinal cancer, prostate cancer, blood cancer and the like.
Although Compounds A and B are suited for oral administration, they can hardly been used in a liquid form for intravenous injection or the like because of extremely low solubility in injectable solutions.
The absorptiveness of anticancer agents, when administered orally, sometimes varies depending on individuals; and hence intravenous administration is mainly employed for the treatment of cancer from the viewpoint of reliability, accuracy and safety. The intravenous injection is convenient when a patient is unable to accept the oral administration. Under the conditions, anticancer agents useful as an injection have been demanded in the field of clinical medicine.
The purpose of the present invention is to provide novel compounds having a potent anticancer activity which are water-soluble and injectable.
The present inventors have synthesized and investigated into various compounds, during which they found that compounds of the formula [I] below are water-soluble and have extremely high anticancer activity among them, and thus completed the present invention.
The present invention relates to the following (1)-(10).
(1) A compound of the formula [I] or a salt thereof:
Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x83xe2x80x83[1]
wherein
A is optionally substituted heteroaryl or its oxide;
B is optionally substituted ethenylene;
D is optionally substituted phenylene; and
E is a group of the formula: 
wherein G is optionally substituted phenyl; and R is optionally substituted heteroaryl or heteroarylmethyl, or a group of the formula: 
wherein n is an integer of 1 to 5; R5 and R6 are same or different and independently selected from the group consisting of hydrogen, C1xe2x80x94C6 alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 taken together with the adjacent nitrogen atom may form a 5- to 7-membered cyclic amino group for xe2x80x94NR5(R6) which may optionally be substituted and, in addition to the nitrogen atom, may optionally comprise an oxygen, sulfur or nitrogen atom as a ring-composing member.
(2) The compound of the formula [I] mentioned in the above (1) or a salt thereof, wherein A is 4-pyridyl or 1-oxido-4-pyridyl; B is ethenylene; D is optionally substituted phenylene; and E is the group of the formula: 
wherein R and G are the same as defined in claim 1.
(3) The compound of the formula [I] mentioned in the above (1) or a salt thereof, wherein A is 4-pyridyl or 1-oxido-4-pyridyl; B is ethenylene; D is optionally substituted phenylene; E is the group of the formula: 
wherein G is optionally substituted phenyl and R is the group of the formula: 
wherein n, R5 and R6 are the same as defined in claim 1.
(4) The compound mentioned in the above (3) or a salt thereof, wherein R5 and R6 are same or different and independently selected from the group consisting of hydrogen, C1xe2x80x94C6 alkyl; or R5 and R6 taken together with the adjacent nitrogen atom may form an optionally substituted 5- to 6-membered cyclic amino group for xe2x80x94NR5(R6).
(5) The compound of the formula [I] mentioned in the above (1) or a salt thereof, wherein A is 4-pyridyl or 1-oxido-4-pyridyl; B is ethenylene; D is phenylene; and E is a group of the formula: 
wherein G is optionally substituted phenyl; and R is optionally substituted 5- to 6-membered heteroaryl or heteroarylmethyl.
(6) The salt mentioned in the above (1), wherein the salt is hydrochloride.
(7) A pharmaceutical composition comprising a compound of the formula [1] in the above-mentioned (1) or a salt thereof as an active ingredient.
(8) The pharmaceutical composition of the above-mentioned (7) which is in a form of injection.
(9) An anticancer agent comprising a compound of the formula [I] in the above-mentioned (1) or a salt thereof as an active ingredient.
(10) The anticancer agent of the above-mentioned (9) which is in a form of injection.
The structural feature of the compound of the present invention is that phenyl in the stilbazole nucleus carries an aminoacylamino group, or a heteroaroylamino group or a heteroaroylaminomethyl group containing nitrogen atom.
The compound having the above structural feature is a novel compound never documented heretofore. The compound of the present invention has a superior anticancer activity with a low toxic potential.
The present invention will hereinafter be described in detail.
Terms herein used to show various substituents are defined below.
Examples of xe2x80x9cphenylenexe2x80x9d group include 1,2-phenylene, 1,3-phenylene and 1,4-phenylene. The phenylene group may have one or two substituents at an arbitrary position(s), examples of which include hydroxy, halogen, amino, C1xe2x80x94C6 alkyl and C1xe2x80x94C6 alkoxy. Among others, optionally substituted 1,2-phenylene, especially non-substituted 1,2-phenylene, is preferred.
The ethenylene group may have a substituent(s) at each carbon atom, examples of which include cyano, bromo and C1xe2x80x94C6 alkyl. Among others, optionally substituted ethenylene, especially non-substituted ethenylene, is preferred.
The term xe2x80x9cheteroarylxe2x80x9d refers to a 5- to 6-membered heteroaryl group having one to two nitrogen atoms as the ring-composing member. The heteroaryl group optionally has one or two substituents at an arbitrary position(s), examples of which include halogen, C1xe2x80x94C6 alkyl, C1xe2x80x94C6 alkoxy, hydroxy and C1xe2x80x94C6 aminoalkyl. The heteroaryl for A includes 6-membered heteroaryl, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl and pyrazinyl. Among others, non-substituted 4-pyridyl is preferred. The heteroaryl for R includes a 5- to 6-membered one, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1-imidazolyl, 2-imidazolyl and 4-imidazolyl.
The term xe2x80x9calkylxe2x80x9d refers to a straight or branched alkyl group of 1-6 carbons, and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, and the like. Among others, C1xe2x80x94C3 alkyl, especially methyl is preferred.
The alkyl moiety of xe2x80x9chydroxyalkylxe2x80x9d and xe2x80x9caminoalkylxe2x80x9d is as defined above.
Examples of xe2x80x9ccyclic aminoxe2x80x9d include, for example, pyrrolidin-1-yl, piperidino, hexamethylenimino, tetrahydropyridin-1-yl, octahydroazosin-1-yl, piperazin-1-yl, homopiperazin-1-yl, morpholino and thiomorpholino. The cyclic amino may have one or two substituents selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl and a heterocyclic group having a nitrogen atom, at any position. Among others, non-substituted pyrrolidin-1-yl, piperidino, morpholino as well as piperazin-1-yl substituted with pyridyl are preferred.
Examples of xe2x80x9chalogenxe2x80x9d include fluorine, chlorine, bromine, iodine and the like.
The xe2x80x9cphenylxe2x80x9d group may have one or two substituents, for example, hydroxy or C1xe2x80x94C6 alkoxy. Among others, phenyl substituted with alkoxy, especially 4-methoxyphenyl, is preferred. The alkylene represented by xe2x80x9cxe2x80x94(CH2)nxe2x80x94xe2x80x9d may have a substituent selected from the group consisting of amino or C1xe2x80x94C6 alkyl at any position.
The term xe2x80x9calkoxyxe2x80x9d refers to a straight or branched alkoxy group of 1-6 carbons, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, and the like. Among others, C1xe2x80x94C3 alkoxy, especially methoxy, is preferred.
The term xe2x80x9calkenylxe2x80x9d refers to a straight or branched alkenyl group of 2-6 carbons, and includes, for example, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 2-butenyl, 3-butenyl, isobutenyl, methalyl, prenyl, isoprenyl, 1,1-dimethylallyl, and the like. C2xe2x80x94C4 alkenyl is especially preferred.
The term xe2x80x9calkynylxe2x80x9d refers to a straight or branched alkynyl group of 2-6 carbons, and includes, for example, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 3-methyl-2-butynyl, and the like. C2xe2x80x94C4 alkynyl is especially preferred.
The term xe2x80x9carylxe2x80x9d refers to an aryl of 6-10 carbons, for example, phenyl, 1-naphthyl and 2-naphthyl.
The term xe2x80x9caralkylxe2x80x9d refers to an aralkyl of 7-8 carbons, for example, benzyl and phenethyl.
The term xe2x80x9chetero ring having nitrogen atomxe2x80x9d refers to the above-mentioned cyclic amino or heteroaryl. Such hetero ring may have one or two substituents selected from the group consisting of alkyl, amino, hydroxy and oxo.
The salts of a compound [1] which fall within the scope of the invention include pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid; organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid and camphorsulfonic acid.
The compound of the present invention may exist in cis (Z) and trans (E) forms. The respective isomers and their mixtures also fall within the scope of the present invention. Among others, E-form is preferred.
Among the compound of the invention of the formula [I], compounds are preferred wherein A is optionally substituted pyridyl or 1-oxidopyridyl, especially non-substituted 4-pyridyl or 1-oxido-4-pyridyl; B is ethenylene with a trans-form, especially non-substituted ethenylene with a trans-form; D is non-substituted 1,2-phenylene; and E is 4-substituted phenyl with preference for 4-alkoxy phenyl, especially 4-alkoxy phenyl.
(E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)-N-piperidinoacetylamino)phenyl)ethenyl)pyridine 1-oxide hydrochloride (the compound of Example 5), (E)-4-(2-(2-(N-(N,N-dimethylglycyl)-N-(4-methoxybenzenesulfonyl)amino)phenyl)ethenyl)pyridine 1-oxide hydrochloride (the compound of Example 8), (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)-N-(4-(2-pyridyl)piperazino)acetylamino)phenyl)ethenyl)pyridine 1-oxide dihydrochloride (the compound of Example 9), (E) -4-(2-(2-(N-(4-methoxybenzenesulfonyl)-N-morpholinoacetylamino)phenyl)ethenyl)pyridine 1-oxide hydrochloride (the compound of Example 13) and (E)-4-(2-(2-(N-(4-methoxybenzenesulfonyl)-N-pyrrolidinoacetylamino)phenyl)ethenyl)pyridine 1-oxide hydrochloride (the compound of Example 14) are preferred for the present invention.
The compound of the present invention can be synthesized according to the processes illustrated below. 
wherein A, B, D, G and R are as defined above.
A compound [3] and a carboxylic acid [4] are subjected to direct condensation reaction using a condensing agent according to the per se known method to give the compound [1]. The reaction can be carried out in the presence of a condensing agent such as N,N-dicyclohexylcarbodiimide (DCC), carbonyldiimidazole or diphenylphosphoryl azide (DPPA) in a suitable solvent (e.g., halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran and dioxane; acetonitrile; N,N-dimethylformamide (DMF), or the like), at about xe2x88x9230xc2x0 C. to about 180xc2x0 C. If necessary, 4-dimethylaminopyridine (DMAP) or 4-pyrrolidinopyridine (4-PPY) may be used as a catalyst. Based on 1 mole of the compound [3], from equimolar to a slightly excess amount of a compound [4] and a condensing agent (e.g., DCC) can be used. When a catalyst is used, the amount can be from 0.1 to 1 mole, based on 1 mole of the compound [3]. The reaction time depends on the kinds of the materials, the solvent, reaction temperature, or the like to be used in the reaction, but is normally from about 5 minutes to 70 hours.
Alternatively, the compound [1] can be prepared by reacting a compound [3] with a reactive derivative of a carboxylic acid [4] in an appropriate solvent. The reaction solvent may be any kind of solvent that does not interfere with the reaction, for example, ethers such as tetrahydrofuran, dioxane and diethyl ether; hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as methylene chloride and chloroform; ketones such as acetone and methyl ethyl ketone; aprotic solvents such as N,N-dimethylformamide (DMF), N,N-dimethyl acetamide, pyridine or acetonitrile, or various mixtures of such solvents. The reactive derivative of a carboxylic acid includes those which are conventionally used such as acyl halides, carboxylic anhydrides, activated amides and activated esters. Above all else, the acyl halides are preferred. Such acyl halides include acyl chlorides and acyl bromides. The acid anhydrides include the mixed anhydrides prepared from monoalkylcarbonic acids and mixed anhydrides prepared from aliphatic carboxylic acids (e.g. acetic acid, pivalic acid, valeric acid, isovaleric acid, trifluoroacetic acid, etc.), and the symmetric anhydrides. The activated amides include such acid amides as imidazole, pyrazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole, and benzothiazole. The activated esters include such esters as the methyl ester, methoxymethyl ester, propargyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, methanesulfonyl ester, N-hydroxysuccinimide and N-hydroxyphthalimide.
When an acyl halide is used in the present process, the reaction is preferably conducted in the presence of a suitable base. Examples of such a base include alkali metal compounds such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and sodium methylate, and organic tertiary amines such as pyridine, triethylamine and triethylenediamine. The reaction can proceed at room temperature in many instances; but it can be carried out under cooling or heating at temperature range of between xe2x88x9278xc2x0 C. and 150xc2x0 C., preferably 0xc2x0 C. and 120xc2x0 C., when necessary. The proportion of the compound [4] based on the compound [3] is preferably 1 through 10 molar equivalents and more preferably 1 through 3 molar equivalents. The reaction time depends on the starting compounds, solvent, reaction temperature, and the like, to be employed, but is normally from about 5 minutes to 70 hours. The compound [1] can be also prepared by Mitsunobu reaction (see, Synthesis 981, 1). 
wherein A, B, D, R and G are as defined above and X is halogen,
The compound [1] of the present invention can be prepared by reacting a compound [5] with a compound [6] in an appropriate solvent. The reaction can be carried out substantially in the same procedure as that used for the reaction between a reactive derivative of carboxylic acid and a compound [3] in Process 1 above.
The resulting compound [1] thus produced can be isolated and purified by the per se known procedures such as concentration, pH adjustment, redistribution, solvent extraction, crystallization, recrystallization, fractional distillation, and chromatography.
The starting compound [3] can be prepared in accordance with a known process (WO95/27699).
The starting compound of the formula [4] wherein R is xe2x80x94(CH2)nxe2x80x94NR5R6 (compound [4a]), among others, can be prepared according to the reaction scheme below as hereinafter described in the Reference Example. 
wherein R5, R6, n and X are as defined above and Ra is a protecting group for a hydroxy group.
As for the starting compounds of the formula [4] wherein R is heteroaryl or heteroarylmethyl, among others, can be commercially available heteroaryl carboxylic acids or heteroaryl acetic acids, or derivatives thereof, or those which can be produced from the existing ones according to a per se known procedure.
The starting compounds [5] can be prepared according to the following reaction scheme. 
wherein B, D and R are as defined above; A0 is heteroaryl corresponding to A; A1 is oxide of A0; and Rb is a leaving group.
Examples of the leaving group include chloro, bromo, iodo, hydroxy group, alkoxycarbonyloxy group, and the like.
The compound [10a] is reacted with the compound [4b] in an appropriate solvent to obtain the compound [5a] corresponding to a compound of the formula [5] wherein A is heteroaryl. The reaction can be carried out substantially in accordance with the method used in Process 1 above. The compound [10a] may be converted into the oxide [10b] by reacting with an organic peroxide in accordance with a procedure known in a text (Jikken Kagaku Koza 21, Yukikagobutsu-no-Gosei III (Part 2), p. 295, 1958) before subjecting to the reaction with the compound [4b], which gives the compound [5b] corresponding to a compound of the formula [5] wherein A is the oxide of heteroaryl.
The compounds wherein R is xe2x80x94(CH2)nxe2x80x94NR5R6 can also be prepared according to the following reaction scheme. 
wherein A0, A1, B, D, R5, R6, n, X and Rb are as defined above.
The compound [12a] can be prepared by reacting the compound [10a] with the compound [11] in an appropriate solvent in the same manner as Process 1; however, when the compound [11] is a reactive derivative of carboxylic acid, a base is needed. The compound [12a] is reacted with the amine [8] in an appropriate solvent optionally in the presence of a base at 0xc2x0 C. to 160xc2x0 C., preferably, at 10xc2x0 C. to 120xc2x0 C. to yield the compound [5c] corresponding a compound of the formula [5] wherein R is xe2x80x94(CH2)nxe2x80x94NR5R6 and A is heteroaryl. If desired, the compound [12a] can be reacted with an organic peroxide by a method described in a text (Jikken Kagaku Koza 21, Yukikagobutsu-no-Gosei, III, Part 2, p. 295, 1958) to give the oxide [12b], which in turn reacted with the compound [8] by the same procedure as that used for the reaction between the compound [8] and the compound [12a] to give the compound [5d] corresponding to a compound of the formula [5] wherein R is xe2x80x94(CH2)nxe2x80x94NR5R6 and A is the oxide of heteroaryl.
The compound [5d] can also be prepared according to the following reaction scheme. 
wherein A0, A1, B, D, R5, R6, n, and Rb are as defined above.
The compound [13a] is converted into the compound [13b] by the same procedure as that used for the conversion of the compound [12a] into the compound [12b]. The compound [13b] is then reduced according to a method known in a text (Shin-Jikken Kagaku Koza 14, Yukikagobutsu-no-Gosei, Part 3, p. 1333, 1978) to yield the compound [10b]. The compound [10b] and the compound [14] are reacted by the same procedure as the reaction between the compound [10b] and the compound [4b] to yield the compound [5d].
The starting compounds [4b] and [11] are either commercially available or prepared in the same manner as Reference Example.
The starting compounds [6], [7] and [8] are commercially available.
The starting compound [10a] can be prepared according to the method described in WO95/27699.
In the processes above, an amino or hydroxy group may be optionally protected with a conventional protecting group before subjecting the compounds to the reaction. The deprotection can be effected at an appropriate stage by the per se known method such as acid treatment, alkaline treatment or catalytic reduction.
Examples of amino-protecting groups include benzyl, benzyloxycarbonyl and trifluoroacetyl. Examples of hydroxy-protecting group include methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, tetrahydropyranyl, tert-butyl, benzyl, trimethylsilyl and tert-butyldimethylsilyl.
The salts of the compounds [1] of the present invention can be produced by the per se known method. For example, a hydrochloride of the compounds [1] of the present invention can be prepared by treating a compound [1] with a solution of hydrogen chloride in alcohol or ethyl ether and recovering the crystalline precipitates by filtration. In case that there are no/little crystalline precipitates, the solution can be concentrated and the deposited crystals are filtered off.
When the compound of the invention is administered as a medicine, it can be administered to mammals inclusive of humans as it is or as a pharmaceutical composition containing the compound in a pharmaceutically acceptable, nontoxic and inert carrier at a concentration of, for example, 0.1% to 99.5%, preferably 0.5% to 90%.
Examples of carrier usable include solid, semisolid, or liquid diluents, fillers, and other formulation auxiliaries, and at least one of them is employed. The pharmaceutical composition is preferably administered in a unit dosage form. The compound of the present invention is water-soluble, and can be used in the form of solutions (e.g., injection for intravenous or intracystic administration or syrup for oral administration), as well as in the solid form. The pharmaceutical composition of the present invention can be administered into tissues (hereinafter, referred to as xe2x80x9cparenteral administrationxe2x80x9d), orally, locally (e.g. transdermally) or rectally. A dosage form suited for each administration mode is of course employed. For instance, the intravenous administration is especially preferred.
The dosage of the compound as an anticancer drug should preferably be adjusted in consideration of conditions of the patient such as age, body weight, nature and severity of disease, as well as the route of administration; but the daily dosage of the compound of the present invention as an active ingredient for adult for intravenous administration can generally be 0.1 mg -1,000 mg, preferably 1 mg -500 mg. The dose range above is not critical and a lower dosage may be sufficient in some cases, while a higher dosage beyond the said range may be needed in other cases. The daily dosage is preferably administered in one time, in general. The composition of the present invention can be also administered continuously or intermittently.
Parenteral administration can be carried out using a liquid unit dosage form, such as a solution, for subcutaneous, intramuscular or intravenous administration. Such a dosage form can be prepared by dissolving a predetermined amount of the compound in a nontoxic liquid vehicle for injection, such as an aqueous or oily vehicle, and sterilizing the solution. Alternatively, it can be prepared by dispensing a predetermined amount of the compound in each vial, sterilizing the vial and contents, and sealing the vial. For extemporaneous dissolution or blending, a powdery or lyophilized active compound may be accompanied by a spare vial and a vehicle. To isotonize an injection, a nontoxic salt or salt solution can be added. In addition, stabilizers, preservatives, emulsifiers, and other additives may also be concomitantly used.
Oral administration can be carried out using a solid or liquid unit dosage form, such as bulk powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets, suppository and other forms. Bulk powders are prepared by comminuting the active substance to a suitable particle size. Powders are prepared by comminuting the active substance to a suitable size and blending the resulting powder with similarly comminuted pharmaceutical carriers such as edible carbohydrates, e.g. starch, mannitol, etc., and other substances, if any. Where necessary, flavorants, preservatives, dispersing agents, colorants, perfumes, etc. can be added.
Capsules are manufactured by encapsulating comminuted bulk particles, powders, or granules obtained in the manner described below for tablets in gelatin or other capsule shells. A lubricant or fluidizing agent, e.g. colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol, etc., can be added to the powdery materials prior to encapsulation. The medicinal efficacy of a capsule after ingestion may be improved by adding a disintegrator or a solubilizer, e.g. carboxymethylcellulose, carboxymethylcellulose calcium, low-substitution-degree hydroxypropylcellulose, croscarmellose sodium, carboxystarch sodium, calcium carbonate, and sodium carbonate.
The finely pulverized powder may be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin or a surfactant and packaged in gelatin sheet to provide soft capsules. Tablets can be manufactured by preparing a powdery composition, granulating or slugging it, adding a disintegrator or a lubricant thereto, and compressing the mixture. The powdery composition can be prepared by mixing a properly comminuted substance with a diluent or a base mentioned above, which may further contain, where necessary, a binder (e.g. carboxymethylcellulose sodium, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc.), a dissolution retardant (e.g. paraffin, wax, hydrogenated castor oil, etc.), a reabsorption promoter (e.g. quartenary salts), and an adsorbent (e.g. bentonite, kaolin, dicalcium phosphate, etc.). The powdery composition can be granulated by wetting the material with a binder, e.g. a syrup, a starch paste, a solution of gum arabic or cellulose, or a polymer solution and, then, passing the wet mass through a sieve by force. The powder, without being granulated, can be compressed with a tablet machine to give slugs of crude form, which is then crushed to give granules.
The granules thus obtained can be protected against inter-adhesion by adding a lubricant such as stearic acid, a salt of stearic acid, talc or mineral oil. The lubricated granules are then compressed into tablets.
The resulting bare tablets can be film-coated or sugar-coated.
Without being subjected to the above granulation or slugging process, the drug may be directly compressed after mixing with a free-flowing inert carrier. A transparent or translucent protective coat comprising a hermetic shellac film, a sugar or polymer coat, or a wax glaze coat can also be applied.
Other oral dosage forms such as solutions, syrups and elixirs. can also be provided in unit dosage forms each containing a predetermined amount of the drug. A syrup can be manufactured by dissolving the compound in a suitable pleasantly flavored aqueous vehicle, while an elixir can be manufactured using a nontoxic alcoholic vehicle.
Where necessary, a unit dose formulation for oral administration may be microencapsulated. This formulation can also be coated with, or embedded in, a polymer, a wax, or the like to provide a prolonged action or sustained release of active ingredient.
Rectal administration can be carried out by using suppositories which can be manufactured by mixing the compound with a water-soluble or -insoluble low-melting solid base, such as polyethylene glycol, cacao butter, or a higher ester (e.g. myristyl palmitate), or a mixture of them.
Best Mode of Practicing the Invention
The following Examples for the preparation of starting compounds (Reference Examples) and the compounds of the present invention (Examples), as well as Formulation Examples and Test Examples are provided to further illustrate the present invention in more detail, which should not be interpreted in any way as to limit the scope thereof. The specific rotation was measured at 20xc2x0 C.